KR920003691B1 - Process for the preparation of benzimidazole derivatives - Google Patents

Abstract

A process for preparing 5- methoxy-2-⇔4- methoxy-3,5dimethyl- 2-pyridyl) methyl! sulfinyl! benzimidazole of formula (I) and its metal salt comprises reacting an alkylthioformimidate deriv. of formula (III) with an anisole deriv. of formula (IV) to obtain a cpd. of formula (II), oxidizing (II) to form a cpd. of formula (I), and converting (I) to its metal salt. In the formulas, R=Me or Et; R1 and R2 each = Cl, Br, I or an amine gp.; one of R1 and R2 is a halogen and the other is an amine. Pref. the oxidizing agent is magnesium salt of monoperoxy phthalic acid. The cpd. (I) and its metal salt are useful as an antiulcer drug.

Description

Method for preparing benzimidazole derivatives

The present invention provides a novel preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] benzimidazole and its metal salt represented by the formula (I). As a method, the compound is a known compound that inhibits gastric acid secretion and is useful for treating gastrointestinal diseases including gastric ulcer, duodenal ulcer and gastritis.

Methods for preparing the compound of formula (I) are described in US Pat. No. 4,255,431, EP 5,129, and the like, and these preparation methods can be summarized as follows.

1. A method of obtaining the compound of formula (I) by oxidizing the compound of formula (II).

2. A method for preparing a compound of formula (I) by reacting a compound of formula (III) with a compound of formula (IV).

(Wherein M is potassium, sodium or lithium as the metal and Z is a reactive esterified hydroxy group)

3. A method of preparing the compound of formula (II) by reacting a compound of formula (V) with a compound of formula (VI) and oxidizing it to produce a compound of formula (I).

( ^One of Z ¹ and Z ² in the above formula is SH (mercapto) group and the other is a reactive esterified hydroxy group)

4. A method for preparing a compound of formula (II) by reacting a compound of formula (VII) with a compound of formula (VII) and oxidizing it to produce a compound of formula (I).

In the above methods, the yield is low and the reaction process is cumbersome, such as making a metal salt such as formula (III), and the preparation of intermediates is difficult, and the target compound of formula (I) reacts during the oxidation process of the compound of formula (II). It is difficult to obtain pure by decomposing to the unreacted oxidant in the liquid.

A feature of the present invention is to prepare the target compound of the structural formula (I) and the metal salt thereof in a high yield and high purity with a simple manufacturing method.

Metal thiocyanate of formula (VII) and a lower alcohol having C ₁ -C ₃ as the starting material using 3,5-dimethyl-4-methoxy-2-halomethylpyridine of formula (VII) as a known compound, or 3, 5-dimethyl-4-methoxy-2-thio of formula (XI) at high yield by reaction at 0 ° C. to reflux condition for 1-3 hours in an aprotic polar solvent such as DMSO, DMF, CH ₃ CN, etc. Obtain cyanomethylpyridine.

After dissolving the compound of formula (XI) prepared as described above in a low alcohol solvent, preferably methanol or ethanol, of C ₁ -C ₃ carbon atoms in anhydrous conditions, and then cooled the solution to 0-10 ℃ in a nitrogen stream The reaction was carried out by passing dry hydrogen chloride gas for 2-5 hours and standing at 0-10 ° C. for 10-25 hours to react with alkyl-[[2- (3,5-dimethyl-4-methoxy) pyridinyl of formula (XII). ] Methylthio] formimidate is obtained in high yield in hydrochloride or base form.

The compound of formula (XII) prepared as described above is relatively known in a solvent such as methanol, ethanol, and 3-amino-4-chloroanisole or 3,4-diaminoanisole of general formula (XIII), which are known compounds. A simple reaction and treatment with an alkali solution such as potassium hydroxide, sodium hydroxide, etc. is an economical way to produce the compound of formula II in high yield. In addition, in the present invention, in order to solve the disadvantage that the target compound of formula (I) is decomposed by the unreacted oxidizing agent in the reaction liquid and cannot be obtained purely in the previous oxidation process reaction, it is not irritating, easy to handle, and mild in oxidizing power. Almost no side reactions occur, and it is very well dissolved in a solvent such as water, so that the reaction conditions are simple, and monoperoxy of the formula (XIV), a known substance that can easily remove unreacted oxidant and by-product magnesium phthalate after the reaction It is a feature of the present invention to obtain a high yield and high purity when the compound of formula (II) is oxidized using magnesium phthalate salt (MMPP) to obtain the target compound of formula (I) and its metal salt.

Scheme of the present invention by the reaction scheme is as follows.

(L is a halogen element such as chlorine, bromine, iodine, M is potassium or sodium, R is methyl, ethyl, and one of R 'and R "is a halogen element such as chlorine or bromine, iodine and the other Is an amine group, or both R 'and R "are amine groups.)

Hereinafter, the present invention will be described in more detail with reference to the following examples.

Example 1

Preparation of 3,5-dimethyl-4-methoxy-2-thiocyanomethylpyridine (XI): 18.56 g (0.1 mol) of 2-chloromethyl-4-methoxy-3,5-dimethylpyridine was added to 100 ml of ethanol. Dissolve and add 10.69 g (0.11 mol) of metal thiocyanate at 0-5 ° C. in small portions for 30 minutes. Crystals are formed at the start of the reaction. The reaction is terminated by further stirring at 0-5 ° C. for 30 minutes, heating and refluxing for 3 hours. At the end of the reaction, the mixture was cooled to 0-5 c, filtered to remove crystals, and the solvent was distilled off under reduced pressure. 100 ml of water is added to the residue to dissolve it, and 300 ml of chloroform is extracted twice. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 19.9 g (95.5%) of the title compound.

Elemental Analysis Value (C ₁₀ H ₁₂ N ₂ OS)

Theoretical value (%): C; 57.67, H; 5.80, N; 13.45

Found (%): C; 57.72, H; 5.89, N; 13,53

Example 2

Preparation of methyl-[[[2- (3,5-dimethyl-4-methoxy) pyrimidyl] methyl] thio] formimidate (XII) dihydrochloride:

After dissolving 20.9 g (0.1 mol) of 3,5-dimethyl-4-methoxy-2-thiocyanomethylpyridine in a mixed solvent of 80 ml of anhydrous methanol and 160 ml of ether, the solution was cooled to 0-10 ° C. in a nitrogen stream. Pass 7.3 g of hydrogen chloride gas for 3 hours and leave the solution for 25 hours at 0-5 ℃ in a closed container. The solvent was distilled off under reduced pressure, 150 ml of anhydrous ether was added to the concentrated residue and triturated to give 24.1 g (76.9%) of the title compound as anhydrous crystals.

Elemental Analysis Value (C ₁₁ H ₁₆ N ₂ O ₂ S · 2HCI)

Theoretical value (%): C; 42.18, H; 5.79, N; 8.94

Found (%): C; 43.21, H; 5.84, N; 9.01

Example 3

Preparation of Methyl-[[[2- (3,5-dimethyl-4-methoxy) pyrimidyl] methyl] thio] formimidate (XII):

After reacting under the conditions of Example 2, the solvent was distilled under reduced pressure, 300 ml of cooling water containing 55 g of potassium carbonate was poured into the concentrated residue, and the mixed solution was extracted three times with 450 ml of chloroform containing 20% methanol. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 21.4 g (89%) of the title compound.

Elemental Analysis Value (C ₁₁ H ₁₆ N ₂ O ₂ S)

Theoretical value (%): C; 54.98, H; 6.71, N; 11.66

Found (%): C; 55.23, H; 6.81, N; 11.72

Example 4

Preparation of 5-methoxy-2-[[[4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] benzimidazole (II):

32.9 g (0.1 mol) of methyl-[[[(2- (3,5-dimethyl-4-methoxy) pyridinyl] methyl] thio] formimide (XII) dihydrochloride and 3-amino in 400 ml of methanol 16.7 g (0.106 mol) of -4-chloroanisole was added and stirred at room temperature for 18 hours, and then refluxed for 6 hours After cooling to 0-10 ° C., sodium hydroxide solution (8.2 g / 160 ml of water) was slowly added to the mixture. The resulting mixture was further refluxed for 80 minutes, and when the reaction was completed, the mixture was distilled under reduced pressure to remove methanol, dissolved in 200 ml of ice water, and extracted with 600 ml of chloroform twice. Filter and remove the solvent under reduced pressure, add 200 ml of acetone and 30 ml of water to the residue, dissolve it, add 21 ml of 17.5% aqueous hydrochloric acid solution at 10-20 ℃ for 20 minutes, cool to 0-5 ℃, and stir for 2 hours. The resulting crystals are filtered off Washing with 30 ml tons and drying gives 27 g of the title compound as hydrochloride.

Dissolve 27 g of the hydrochloride obtained above in 100 ml of water and add 300 ml of chloroform. While stirring, 115 ml of 15% aqueous sodium carbonate solution is added to neutralize and the organic layer is separated. After drying over anhydrous magnesium sulfate, filtration, distillation under reduced pressure to remove the solvent, 60 ml of methyl ethyl ketone was added to the concentrated residue to dissolve, petroleum ether was slowly added, cooled to 0-5 ° C. and stirred for 5 hours to form crystals. The resulting crystals were filtered off, washed with 30 ml of ether and dried to give 21 g (63.7%) of the title compound as white crystals.

Melting Point: 118-123 ℃

: 3,341, 1,212, 1,167

: 3,341, 1,212, 1,167

¹ H-NMR (CDCI ₃ ) δ: 2.06 (s, 3H), 2.11 (s, 3H), 3.56 (s, 3H), 3.65 (s, 3H), 4.72 (s, 2H), 6.6-7.5 (m , 3H), 8.16 (s, 1H)

Example 5

Preparation of 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl) methyl] thio] benzimidazole (II):

3.29 g (0.01 mol) and 3,4 of methyl-[[[(2- (3,5-dimethyl-4-methoxy) pyridinyl] methyl] thio] form-imdate (XII) dihydrochloride in 40 ml of methanol -A mixture of 1.75 g (0.01 mol) of diaminoanisole hydrochloride is reacted by stirring at room temperature for 20 hours, to which sodium hydroxide solution (1.3 g / 20 ml of water) is added and the resulting mixture is refluxed for 1 hour. Upon completion of the reaction, the reaction was carried out in the same manner as in Example 4 to obtain 2.4 g (73%) of the title compound.

Melting Point: 119-123 ℃

: 3,341, 1,212, 1,167

: 3,341, 1,212, 1,167

¹ H-NMR (CDCI ₃ ) δ: 2.06 (s, 3H), 2.11 (s, 3H), 3.56 (s, 3H), 3.65 (s, 3H), 4.72 (s, 2H), 6.6-7.5 (m , 3H), 8.16 (s, 1H)

Example 6

Preparation of 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] benzimidazole (I):

A solution of 30 g (0.055 mol) of 90% monoperoxyphthalic acid salt hexahydrate in 150 ml of water was dissolved in 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl]. 32.9 g (0.1 mol) of thio] benzimidazole was added to a solution of 60 ml of ethanol at room temperature for 3 minutes, and the mixture was stirred at 45-50 ° C. for 2 hours to react. After the reaction was completed, the mixture was cooled to 0-5 ° C., and 38 ml of 20% aqueous sodium carbonate solution was slowly added thereto, and the mixture was extracted with two portions of 400 ml of chloroform. The organic layer was dried over anhydrous magnesium sulfate at -5-0 占 폚, filtered, and the solvent was removed by distillation under reduced pressure at a temperature of 10 占 폚 or lower. 120 ml of acetonitrile were added to the residue, and stirred for 1 hour at -5-0 ° C to produce crystals and filtered. The filtered crystals were washed with 10 ml of acetonitrile and 20 ml of ether and dried under reduced pressure at 30 ° C. for 5 hours to give 33.2 g (96%) of the title compound as white crystals.

Melting Point: 154-156 ℃

: 1,413, 1,211, 1,023

: 1,413, 1,211, 1,023

¹ H-NMR (CDCℓ ₃ + DMSO-d ₆ ) δ: 2.10 (s, 3H), 2.13 (s, 3H), 3.60 (s, 3H), 3.76 (s, 3H), 4.6 (s, 2H), 6.68-7.58 (m, 3H), 8.16 (s, 1H)

Example 7

Preparation of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) ethyl] sulfinyl] benzimidazole sodium salt:

A solution of NaOH 4g (0.1 mol) dissolved in 10 ml of deionized water and 350 ml of tetrahydrofuran were mixed with vigorous stirring while 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-pyridyl 34.5 g (0.1 mol) of methyl] sulfinyl] benzimidazole (I) is added and stirring is continued for 1 hour. Add 160 ml of isopropanol to the mixture and stir at room temperature for 18 hours. The mixture is cooled to 0-5 ° C. and stirred for another 3.5 hours, after which the crystals are filtered and washed with 100 ml of isopropanol. The filtered crystals were dried at 45 ° C. for 5 hours under reduced pressure to afford 35.3 g (96%) of the title compound.

Melting Point: 207-210 ℃

¹ H-NMR (D ₆ O) δ: 1.86 (s, 3H), 2.1 (s, 3H), 3.51 (s, 3H), 3.86 (s, 3H), 4.75 (s, 2H), 6.84 (dd, 1H), 7.3 (d, 1H), 7.56 (d, 1H), 8.16 (d, 1H)

Example 8

Preparation of 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] benzimidazole potassium salt:

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] benz with vigorous stirring of a solution of 5.6 g (0.1 mol) of KOH in 300 ml of isopropanol 34.5 g (0.1 mol) of imidazole (I) was added and stirring continued for 30 minutes. Add 200 ml of isopropanol to the mixture and stir for another 2 hours at room temperature. The solvent was distilled off under reduced pressure, 300 ml of dichloromethane and 400 ml of deionized water were added and stirred for 20 minutes. The layers were separated, washed once with 100 ml of dichloromethane, and filtered through celite. The filtrate was removed by evaporation under reduced pressure and recrystallized with 250 ml of ethyl acetate to obtain 35.7 g (93.1%) of the title compound.

Melting Point: 147-150 ℃

Example 9

Preparation of Di-5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] benzimidazole magnesium salt:

1 ml of CCI ₄ was added to 70 ml of anhydrous ethanol, and 1.2 g (0.05 mol) of magnesium was added while stirring to dissolve the solution. 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl ] Sulfinyl] benzimidazole (I) 34.5g (0.1 mol) was added dropwise to the solution dissolved in 700 ml of ethanol for 30 minutes in small portions, stirred for 30 minutes at room temperature, the solvent was distilled under reduced pressure and the resulting crystals were dried. 31.4 g (88%) of compound are obtained as a crystalline solid.

Melting Point: 178-179 ℃

Example 10

Preparation of Di-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] benzimidazole calcium salt dihydrate:

A solution of 5.5 g (0.05 mol) of anhydrous CaC1 ₂ dissolved in 60 ml of deionized water was added to 400 ml of deionized water. 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulphi To a solution of 36.7 g (0.1 mole) of sodium] benzimidazole sodium salt was added dropwise in small portions for 10 minutes with vigorous stirring and further stirred at room temperature for 40 minutes. The resulting precipitate was filtered, washed sufficiently with 500 ml of deionized water, dried at room temperature, triturated and vacuum dried at 45 ° C. for 15 hours to give 32.5 g (85%) of the title compound.

Melting Point: 180-183 ℃

¹ H-NMR (CDCℓ ₃ + DMSO-d ₆ ) δ: 1.99 (s, 3H), 2.14 (s, 3H), 3.6 (s, 3H), 3.58 (s, 3H), 3.69 (s, 3H), 4.47 (s, 2H), 6.7 (dd, 1H), 7.1 (d, 1H), 7.59 (d, 1H), 8.14 (s, 1H)

Claims (5)

A compound of formula (II) is prepared by reacting an alkylthioformimidate derivative of general formula (XII) with an anisole derivative of general formula (XIII), followed by oxidation to prepare a target compound of structural formula (I). A method for producing a compound of formula (I) and a metal salt thereof, characterized by converting the target compound of (I) to a metal salt in a conventional manner.

In the above structural formula, R represents methyl and ethyl group, one of R 'and R "is a halogen element such as chlorine, bromine, iodine, and the other is an amine group or R', R" are both amine groups.) The process of claim 1, wherein the compound of formula (I) is prepared using a monoperoxy phthalate magnesium salt of formula (XIV) as an oxidant in the oxidation reaction of the compound of formula (II).

The compound of formula (XII) according to claim 1, wherein the compound of formula (XII) is reacted with a compound of formula (X) to prepare a compound of formula (XI), which is dissolved in a solution such as methanol or ethanol. Method for producing by reacting chlorine gas.

(Wherein L represents chlorine, bromine or iodine and M represents potassium or sodium element). The method of claim 1, wherein the metal salt of formula (I) is prepared. The method of claim 4 wherein the metal salt is Na ⁺ , K ⁺ , Mg ⁺² , Ca ⁺² .